Integrated proteomic, DNA methylation, and targeted Next Generation Sequencing reveals relevant heterogeneity in lower-grade meningioma and a new target in NF2 mutated meningiomas

Meningiomas, the most common primary brain tumours, are classified by the World Health Organization (WHO) into grades 1, 2, and 3. Some grade 1 tumours exhibit increased clinical aggressiveness with the biallelic mutation of Neurofibromatosis 2 (NF2) being the most frequent mutation reported. In our study, we analysed the most common driver mutations (NF2, AKT1, KLF4, and TRAF7) in meningioma by proteomics and genomics focussing on lower grade tumours. Our genomic data revealed co-occurrences of non-NF2 mutations in lower-grade meningiomas suggesting synergistic effects supporting tumour growth. NF2-/- meningiomas showed distinct proteomic clustering, with different mutations found in these clusters. Additionally, proteomics identified ANXA3 in NF2-/- meningioma and its role in proliferation was confirmed in grade1 and subsequently grade 3 tumours in vitro and with abolished growth when tested in meningioma mouse model. These findings highlight new targets in different meningioma backgrounds presenting ANXA3 as a potential therapeutic target for meningioma treatment